2-26183002-C-G

Variant names:

• chr2-26183002-C-G
• rs199966839
• NM_001168241.2:c.289C>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001168241.2(GAREM2):​c.289C>G​(p.Arg97Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000843 in 1,551,558 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00074 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00085 (2 hom.)
• Consequence: GAREM2 NM_001168241.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.713
• Publications: 3 publications found

Genes affected

GAREM2 (HGNC:27172): (GRB2 associated regulator of MAPK1 subtype 2)

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014363438).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAREM2	NM_001168241.2	c.289C>G	p.Arg97Gly	missense_variant	Exon 3 of 6	ENST00000401533.7	NP_001161713.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAREM2	ENST00000401533.7	c.289C>G	p.Arg97Gly	missense_variant	Exon 3 of 6	1	NM_001168241.2	ENSP00000384593.1
GAREM2	ENST00000407684.1	c.58C>G	p.Arg20Gly	missense_variant	Exon 2 of 6	2		ENSP00000384581.1

Frequencies

GnomAD3 genomes AF: 0.000742 AC: 113 AN: 152194 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000970

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000829 AC: 126 AN: 151960 AF XY: 0.000842

Gnomad AFR exome AF: 0.000126

Gnomad AMR exome AF: 0.000729

Gnomad ASJ exome AF: 0.00531

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000871

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.000854 AC: 1195 AN: 1399364 Hom.: 2 Cov.: 31 AF XY: 0.000853 AC XY: 589 AN XY: 690194

African (AFR) AF: 0.000475 AC: 15 AN: 31598

American (AMR) AF: 0.000644 AC: 23 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.00647 AC: 163 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35738

South Asian (SAS) AF: 0.0000631 AC: 5 AN: 79236

European-Finnish (FIN) AF: 0.000101 AC: 5 AN: 49270

Middle Eastern (MID) AF: 0.00509 AC: 29 AN: 5698

European-Non Finnish (NFE) AF: 0.000810 AC: 874 AN: 1078942

Other (OTH) AF: 0.00140 AC: 81 AN: 57996

GnomAD4 genome AF: 0.000742 AC: 113 AN: 152194 Hom.: 0 Cov.: 33 AF XY: 0.000673 AC XY: 50 AN XY: 74342

African (AFR) AF: 0.000169 AC: 7 AN: 41444

American (AMR) AF: 0.00105 AC: 16 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00519 AC: 18 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000970 AC: 66 AN: 68032

Other (OTH) AF: 0.00143 AC: 3 AN: 2094

Alfa AF: 0.00120 Hom.: 0

Bravo AF: 0.000684

ExAC AF: 0.000461 AC: 12

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 09, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.289C>G (p.R97G) alteration is located in exon 3 (coding exon 3) of the GAREM2 gene. This alteration results from a C to G substitution at nucleotide position 289, causing the arginine (R) at amino acid position 97 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.048	T;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.014	T;T
MetaSVM	Benign	-0.86	T
PhyloP100		0.71
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-4.7	D;D
REVEL	Benign	0.12
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	D;.
Vest4		0.41
MVP		0.56
ClinPred		0.083	T
GERP RS		5.5
Varity_R		0.67
gMVP		0.66
Mutation Taster		=45/55	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs199966839; hg19: chr2-26405871;